Substituted phenylamidines medicaments containing said compounds and method for production thereof

ABSTRACT

The present invention relates to phenylamidines of general formula  
                 
 
     wherein R 6  R 7  are defined as in claim 1, the tautomers, the stereoisomers including mixtures thereof and the salts thereof, particularly their physiologically acceptable salts with inorganic or organic acids or bases, which have valuable pharmacological properties, preferably antithrombotic effects, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

[0001] The scope of protection of WO 96/33970 covers phenylamidines ofgeneral formula

[0002] wherein R¹ denotes inter alia a C₁₋₄-alkyloxycarbonyl group, anaryl-C₁₋₃-alkyloxycarbonyl group or a group of formula

[0003] wherein

[0004] R^(a) denotes a hydrogen atom or an alkyl group and

[0005] R^(b) denotes an alkyl group or a 3- to 7-membered cycloalkylgroup, even though no such compound is specifically described in thispublished application.

[0006] It has now been found that the phenylamidines of general formula

[0007] wherein

[0008] R₆ denotes a hydroxy, C₁₋₁₈-alkyloxycarbonyl, arylcarbonyl oraryl-C₁₋₄-alkyloxycarbonyl group,

[0009] R₇ denotes a hydrogen atom, a C₁₋₈-alkyl, C₄₋₇-cycloalkyl,phenyl-C₁₋₄-alkyl or R₈—CO—OCHR₉-group wherein

[0010] R₈ denotes a C₁₋₄-alkyl, C₁₋₄-alkoxy, C₃₋₇-cycloalkyl orC₄₋₇-cycloalkoxy group and

[0011] R₉ denotes a hydrogen atom or a C₁₋₄-alkyl group,

[0012] the tautomers, the stereoisomers and the salts thereof,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases, also have valuable pharmacologicalproperties, preferably antithrombotic effects.

[0013] The term aryl moieties mentioned in the definition of theabovementioned groups refers to a phenyl group which may in each case bemonosubstituted by R₁₀, mono-, di- or trisubstituted by R₁₁ ormonosubstituted by R₁₀ and additionally mono- or disubstituted by R₁₁,while the substituents may be identical or different and

[0014] R₁₀ denotes a cyano, carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,C₁₋₄-alkylsulphenyl, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, hydroxy,C₁₋₄-alkylsulphonyloxy, trifluoromethyloxy, nitro, amino,C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, C₁₋₄-alkyl-carbonylamino,N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino, C₁₋₄-alkylsulphonylamino,N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulphonyl-amino, aminosulphonyl,C₁₋₄-alkylaminosulphonyl or di-(C₁₋₄-alkyl)-aminosulphonyl group or acarbonyl group which is substituted by a 5- to 7-membered alkyleneiminogroup, while in the abovementioned 6- to 7-membered alkyleneimino groupsa methylene group in the 4 position may in each case be replaced by anoxygen or sulphur atom or by a sulphinyl, sulphonyl, imino orN-(C₁₋₄-alkyl)-imino group, and

[0015] R₁₁ denotes a fluorine, chlorine, bromine or iodine atom or aC₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group or

[0016] two groups R₁₁, if they are bound to adjacent carbon atoms,together denote a C₃₋₅-alkylene, methylenedioxy or1,3-butadien-1,4-ylene group.

[0017] The present invention relates to the compounds of the abovegeneral formula I, the tautomers, the stereoisomers and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases, pharmaceutical compositionscontaining these compounds and processes for the preparation thereof.

[0018] Preferred compounds of the above general formula I are thosewherein

[0019] the substituted amidino group is in the 4 position, particularlythose compounds wherein

[0020] R₆ denotes a hydroxy, C₁₋₁₈-alkyloxycarbonyl, phenylcarbonyl orphenyl-C₁₋₄-alkyloxycarbonyl group and

[0021] R₇ denotes a hydrogen atom, a C₁₋₈-alkyl, C₅₋₇-cycloalkyl orphenyl-C₁₋₄-alkyl group,

[0022] while the abovementioned phenyl moieties may in each case bemono- or disubstituted by R₁₁, the substituents being identical ordifferent, and

[0023] R₁₁ denotes a fluorine, chlorine or bromine atom, a C₁₋₂-alkyl,trifluoromethyl or C₁₋₂-alkoxy group,

[0024] the tautomers, the stereoisomers and the salts thereof.

[0025] Particularly preferred compounds of the above general formula Iare those wherein

[0026] R₆ denotes a hydroxy, C₁₋₁₂-alkyloxycarbonyl, phenylcarbonyl orphenyl-C₁₋₂₋alkyloxycarbonyl group and

[0027] R₇ denotes a C₁₋₈-alkyl or C₅₋₇-cycloalkyl group,

[0028] the tautomers, the stereoisomers and the salts thereof.

[0029] Most preferred compounds of the above general formula I are thosewherein

[0030] R₆ denotes a hydroxy, C₅₋₁₂-alkyloxycarbonyl, phenylcarbonyl orbenzyloxycarbonyl group and

[0031] R₇ denotes a C₁₋₄-alkyl or C₅₋₆-cycloalkyl group,

[0032] the tautomers, the stereoisomers and the salts thereof.

[0033] The following are mentioned as examples of preferred compounds:

[0034] (1)4-[2-[[4-(octyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine,

[0035] (2)4-[2-[[4-(hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine,

[0036] (3)4-[2-[[4-(methyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine,

[0037] (4)4-[2-[[4-(benzoylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazineand

[0038] (5)4-[2-[[4-(hydroxyamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0039] and the salts thereof.

[0040] The new compounds of general formula I may be obtained, forexample, by the following method:

[0041] a. In order to prepare a compound of general formula I wherein R₆has the meanings given hereinbefore, with the exception of the hydroxygroup:

[0042] acylating a compound of general formula

[0043] wherein

[0044] R₇ is as hereinbefore defined,

[0045] with a compound of general formula

Z₁—R₆′  (III),

[0046] wherein

[0047] R₆′ has the meanings given for R₆ hereinbefore, with theexception of the hydroxy group, and

[0048] Z₁ denotes a nucleofugic leaving group such as a halogen atom,e.g. a chlorine atom, or, if R₆′ denotes an arylcarbonyl group, Z₁ mayalso denote a hydroxy group.

[0049] The reaction is preferably carried out in a solvent such asacetone, methylene chloride, tetrahydrofuran, toluene, dioxane oracetonitrile, optionally in the presence of an inorganic or a tertiaryorganic base, preferably at temperatures between −20° C. and the boilingtemperature of the solvent used.

[0050] The reaction with a compound of general formula III wherein Z₁denotes a nucleofugic leaving group is preferably carried out in asolvent such as methylene chloride, acetonitrile, tetrahydrofuran,toluene, acetone or acetone/water, optionally in the presence of a basesuch as potassium carbonate or N-ethyl-diisopropylamine at temperaturesbetween −10 and 60° C., and

[0051] the reaction with a carboxylic acid of general formula III ispreferably carried out in the presence of a dehydrating oracid-activating agent, e.g. in the presence of isobutyl chloroformate,thionyl chloride, trimethylchlorosilane, phosphorus trichloride,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-carbonyldiimidazole or N,N′-thionyldiimidazole,triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethylazodicarboxylate, optionally in the presence of a base such as potassiumcarbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine attemperatures between −10 and 60° C.

[0052] b. In order to prepare a compound of general formula I wherein R₆denotes a hydroxy group:

[0053] reacting a nitrile of general formula

[0054] wherein

[0055] R₇ is as hereinbefore defined, with hydroxylamine or the saltsthereof.

[0056] The reaction is expediently carried out in a solvent such asmethanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran,tetrahydrofuran/water, dioxane or dioxane/water, optionally in thepresence of a tertiary organic base such as triethylamine, attemperatures between 0 and 150° C., e.g. at the boiling temperature ofthe reaction mixture, but preferably at temperatures between 50 and 100°C.

[0057] Moreover, the compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers and the compoundsof general formula I obtained with a double bond may be resolved intotheir cis/trans isomers. Thus, for example, cis/trans mixtures may beresolved into their cis and trans isomers, and compounds with at leastone optically active carbon atom may be resolved into their enantiomers.

[0058] Thus, for example, the cis/trans mixtures obtained may beresolved by chromatography into their cis and trans isomers, thecompounds of general formula I obtained which occur as racemates may beseparated into their optical enantiomers by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) and compounds of general formula I with atleast 2 asymmetric carbon atoms may be resolved into their diastereomerson the basis of their physical-chemical differences using methods knownper se, e.g. by chromatography and/or fractional crystallisation, and,if these compounds are obtained in racemic form, they may subsequentlybe resolved into the enantiomers as mentioned above.

[0059] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-O-p-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be, for example, (+) or(−)-menthol and an optically active acyl group in amides, for example,may be a (+)- or (−)-menthyloxycarbonyl.

[0060] Furthermore, the compounds of formula I may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

[0061] Moreover, if the new compounds of formula I contain a carboxygroup, they may subsequently, if desired, be converted into the saltsthereof with inorganic or organic bases, particularly for pharmaceuticaluse into the physiologically acceptable salts thereof. Suitable basesfor this purpose include for example sodium hydroxide, potassiumhydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

[0062] The compounds used as starting materials are known from theliterature in some cases or may be obtained by methods known from theliterature (see Examples).

[0063] As already mentioned, the new phenylamidines of general formula Iand their salts, particularly their physiologically acceptable saltswith inorganic or organic acids or bases, have valuable properties.Thus, the new phenylamidines of general formula I and their salts havevaluable pharmacological properties, not only an anti-inflammatoryactivity and an inhibiting effect on bone degradation but also, inparticular, antithrombotic and antiaggregatory effects and an inhibitingeffect on tumours and metastases.

[0064] In view of their biological properties the new compounds ofgeneral formula I according to the invention and the physiologicallyacceptable salts thereof are suitable for treating or preventingdiseases in which smaller or greater aggregations of cells occur orcell-matrix interactions play a part, e.g. in combating or preventingvenous and arterial thromboses, cerebrovascular diseases, pulmonaryembolism, cardiac infarct, arteriosclerosis, osteoporosis and themetastasis of tumours, and for treating genetically caused or acquireddisorders of the interactions of cells with one another or with solidstructures. They are also suitable as an accompanying therapy inthrombolysis using fibrinolytics or vascular interventions such astransluminal angioplasty or in the treatment of shock, psoriasis,diabetes and inflammation.

[0065] The compounds of general formula I include in particular newprodrugs of the compound

[0066]A=4-[2-[(4-amidinophenyl)aminocarbonyl]ethyl]-1-carboxymethyl-piperazine(Example 1(2) of WO 96/33970).

[0067] The biological properties of the new compounds were investigatedas follows, for example:

[0068] The concentration of compound A was measured in the plasma afteroral administration of the compound

[0069]B=4-[2-[[4-(hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine(Example 1(1) of the present application).

[0070] After oral administration of 1 mg/kg of compound B to Rhesusmonkeys the concentration of compound A in the plasma was measured 2, 4,8 and 24 hours after administration of the substance. For this purposethe Rhesus plasma was incubated with a suspension of human thrombocytesin plasma and the compound(3S,5S)-5-[(4′-amidino-4-biphenylyl)-oxymethyl]-3-carboxymethyl-pyrrolidin-2-one-[3-³H-4-biphenylyl](³H-BIBU 52, described in DE-A-4,214,245) as ligand. The free and boundligand were separated by centrifugation and quantitatively determined byscintillation counting. The concentration of compound A was calculatedfrom the amount of bound ligand using a calibration curve.

[0071] For this purpose, donor blood is taken from an anticubital veinand anticoagulated with trisodium citrate (final concentration: 13mmol/l). The blood is centrifuged for 10 minutes at 170×g and thesupernatant platelet-rich plasma (PRP) is removed. The remaining bloodis sharply centrifuged off again at 3200×g and the supernatantplatelet-depleted plasma (PDP) is removed.

[0072] For the calibration curve for calculating the concentration, 5 μlof a solution of compound A are added to 995 μl of PDP (finalconcentration 5000 nmol/l). Further plasma samples from this sample arediluted with PDP to give a final concentration of 2.5 nmol/l.

[0073] 10 μl of ³H-BIBU 52 (final concentration 10 nmol/l), 10 μl of¹⁴C-sucrose (370 Bq) and 80 μl of PRP are added to 150 μl of plasmasample from the Rhesus monkey or calibration curve plasma and thepreparations are incubated for 20 minutes at ambient temperature. Thenthe samples are centrifuged for 5 minutes at 2000×g and the supernatantis drawn off. 100 μl of the supernatant are combined with 100 μl of NaOH0.2 mol/l, 15 μl of HCl 5 mol/l and 2 ml of scintillator and the ³H- and¹⁴C-radioactivity are measured quantitatively. The pellet is dissolvedin 200 μl of NaOH 0.2 mol/l. 180 μl thereof are combined with 15 μl ofHCl 5 mol/l and 2 ml of scintillator and the ³H- and ¹⁴C-radioactivityare measured. The residual plasma remaining in the pellet is determinedfrom the ¹⁴C content and removed. The quantity of bound ligand isdetermined from the ³H content. The quantity of bound ligand is plottedagainst the concentration of the calibration curve plasma. Theconcentration of compound A in the Rhesus plasma is calculated from thequantity of bound ligand in the relevant plasma sample compared with thecalibration curve.

[0074] The following Table contains the values found: conc. of A conc.of A conc. of A conc. of A compound in [nM], 2 h in [nM], 4 h in [nM], 8h in [nM], 24 h B 413 316 145 0

[0075] As the results show, after oral administration of 1 mg/kg ofcompound B to Rhesus monkeys, high plasma levels of theanti-thrombotically active compound A are maintained for a period of atleast 8 hours.

[0076] For combating or preventing the illnesses mentioned above, thedose is between 0.1 μg and 30 mg/kg of body weight, preferably 1 μg to15 mg/kg of body weight, administered up to 4 times a day. For this, thecompounds of formula I prepared according to the invention may beformulated, optionally together with other active substances such asthromboxane-receptor antagonists and thromboxane synthesis inhibitors orcombinations thereof, ADP receptor antagonists, clopidogrel,ticlopidine, serotonin antagonists, α-receptor antagonists,alkylnitrates such as glycerol trinitrate, phosphodiesterase inhibitors,prostacycline and their analogues, fibrinolytics such as tPA,prourokinase, urokinase, streptokinase, or anticoagulants such asheparin, dermatane sulphate, activated Protein C, vitamin K antagonists,hirudine, inhibitors of thrombin or other activated clotting factors,together with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol,water/polyethyleneglycol, propyleneglycol, stearylalcohol,carboxymethylcellulose or fatty substances such as hard fat or suitablemixtures thereof, to produce conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions, solutions,sprays or suppositories.

[0077] The Examples that follow are intended to illustrate theinvention:

Preparation of the Starting Compounds: EXAMPLE I

[0078] N-(4-cyanophenyl)-acrylamide

[0079] Prepared by reacting 4-amino-benzonitrile with acrylic acidchloride in methylene chloride in the presence of triethylamine.

[0080] Melting point: 192-194° C. R_(f) value: 0.43 (silica gel;methylene chloride/methanol=20:1)

EXAMPLE II

[0081]4-[2-[(4-cyanophenyl)aminocarbonyl]ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0082] Prepared by reacting N-(4-cyanophenyl)-acrylamide and1-[(ethoxycarbonyl)methyl]-piperazine in toluene at reflux temperature.

[0083] R_(f) value: 0.80 (silica gel; methylene chloride/methanol/conc.aqueous ammonia=9:1:0.1) Mass spectrum: (M+H)⁺=345

EXAMPLE III

[0084]4-[2-[(4-amidinophenyl)aminocarbonyl]ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine-triacetate

[0085] Prepared by catalytic hydrogenation of4-[2-[[4-(hydroxyamidino)phenyl]-aminocarbonyl]ethyl]-1-[(ethoxycarbonyl)methyl]-piperazinein glacial acetic acid at 60° C. in the presence of palladium/charcoal.

[0086] R_(f) value: 0.27 (silica gel; methylene chloride/methanol/conc.aqueous ammonia=4:1:0.1) Mass spectrum: (M+H)⁺=362

Preparation of the End Products: EXAMPLE 1

[0087]4-[2-[[4-(octyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0088] 6.9 g of potassium carbonate are added to 5.4 g of4-[2-[(4-amidinophenyl)aminocarbonyl]ethyl]-1-[(ethoxycarbonyl)methyl-piperazine-triacetatein 150 ml of acetone and 50 ml of water at 0° C. To this mixture 2.9 mlof octyl chloroformate in 10 ml of acetone are added dropwise, withstirring, at a temperature below 7° C. After stirring overnight atambient temperature the mixture is diluted with water and the acetone isdrawn off in vacuo. The residue is extracted with ethyl acetate, washedwith saline solution, dried and evaporated down. The residue is purifiedby chromatography over a silica gel column with methylenechloride/methanol, to which some concentrated aqueous ammonia has beenadded.

[0089] Yield: 2.3 g (45% of theory), Melting point: 136-138° C. R_(f)value: 0.27 (silica gel; methylene chloride/methanol/conc. aqueousammonia=9:1:0.1)

[0090] The following compounds are obtained analogously to Example 1:

[0091] (1)4-[2-[[4-(hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0092] Melting point: 131-134° C. Mass spectrum: (M+H)⁺=490

[0093] (2)4-[2-[[4-(methoxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0094] Melting point: 155-156° C. Mass spectrum: (M+H)⁺=420

[0095] (3)4-[2-[[4-(benzoylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0096] Melting point: 189° C. Mass spectrum: (M+H)⁺=466

EXAMPLE 2

[0097]4-[2-[[4-(hydroxyamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine

[0098] To a solution of 6 g of4-[2-[(4-cyanophenyl)aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazinein 50 ml of ethanol are added 2.4 g of hydroxylamine-hydrochloride and4.8 ml of triethylamine and the mixture is refluxed for 3 hours. It iscooled, the precipitate is suction filtered, washed with ethanol anddried.

[0099] Yield: 5.1 g (77% of theory), Melting point: 182-183° C. Massspectrum: (M+H)⁺=378

EXAMPLE 3

[0100] Tablet Containing 50 mg of Active Substance

[0101] Composition: (1) Active substance  50.0 mg (2) Lactose  98.0 mg(3) Maize starch  50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5)Magnesium stearate  2.0 mg 215.0 mg

[0102] Preparation:

[0103] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side. Diameter of the tablets: 9 mm.

EXAMPLE 4

[0104] Tablet Containing 350 mg of Active Substance

[0105] Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg(3) Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5)Magnesium stearate  4.0 mg 600.0 mg

[0106] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side. Diameter of the tablets: 12 mm.

EXAMPLE 5

[0107] Capsules Containing 50 mg of Active Substance Composition: (1)Active substance  50.0 mg (2) Dried maize starch  58.0 mg (3) Powderedlactose  50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg

[0108] Preparation:

[0109] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0110] This powder mixture is packed into size 3 hard gelatine capsulesin a capsule filling machine.

EXAMPLE 6

[0111] Capsules Containing 350 mg of Active Substance

[0112] Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg430.0 mg

[0113] Preparation:

[0114] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0115] This powder mixture is packed into size 0 hard gelatin capsulesin a capsule filling machine.

1. Phenylamidines of general formula

wherein R₆ denotes a hydroxy, C₁₋₁₈-alkyloxycarbonyl, arylcarbonyl or aryl-C₁₋₄-alkyloxycarbonyl group, R₇ denotes a hydrogen atom, a C₁₋₈-alkyl, C₄₋₇-cycloalkyl, phenyl-C₁₋₄-alkyl or R₈—CO—OCHR₉-group wherein R₈ denotes a C₁₋₄-alkyl, C₁₋₄-alkoxy, C₃₋₇-cycloalkyl or C₄₋₇-cycloalkoxy group and R₉ denotes a hydrogen atom or a C₁₋₄-alkyl group, the term aryl moieties mentioned in the definition of the abovementioned groups referring to a phenyl group which may in each case be monosubstituted by R₁₀, mono-, di- or trisubstituted by R₁₁ or monosubstituted by R₁₀ and additionally mono- or disubstituted by R₁₁, while the substituents may be identical or different and R₁₀ denotes a cyano, carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl, C₁₋₄-alkylsulphenyl, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, hydroxy, C₁₋₄-alkylsulphonyloxy, trifluoromethyloxy, nitro, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, C₁₋₄-alkyl-carbonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino, C₁₋₄-alkylsulphonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulphonyl-amino, aminosulphonyl, C₁₋₄-alkylaminosulphonyl or di-(C₁₋₄-alkyl)-aminosulphonyl group or a carbonyl group which is substituted by a 5- to 7-membered alkyleneimino group, while in the abovementioned 6- to 7-membered alkyleneimino groups a methylene group in the 4 position may in each case be replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl, imino or N-(C₁₋₄-alkyl)-imino group, and R₁₁ denotes a fluorine, chlorine, bromine or iodine atom, a C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group or two groups R₁₁, if they are bound to adjacent carbon atoms, together denote a C₃-₅-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group, the tautomers, the stereoisomers and the salts thereof.
 2. Phenylamidines of general formula I according to claim 1, wherein the substituted amidino group is in the 4 position, the tautomers, the stereoisomers and the salts thereof.
 3. Phenylamidines of general formula I according to claim 2, wherein R₆ denotes a hydroxy, C₁₋₁₈-alkyloxycarbonyl, phenylcarbonyl or phenyl-C₁₋₄-alkyloxycarbonyl group and R₇ denotes a hydrogen atom, a C₁₋₈-alkyl, C₅₋₇-cycloalkyl or phenyl-C₁₋₄-alkyl group, while the abovementioned phenyl moieties may in each case be mono- or disubstituted by R₁₁, the substituents being identical or different, and R₁₁ denotes a fluorine, chlorine or bromine atom, a C₁₋₂-alkyl, trifluoromethyl or C₁₋₂-alkoxy group, the tautomers, the stereoisomers and the salts thereof.
 4. Phenylamidines of general formula I according to claim 2, wherein R₆ denotes a hydroxy, C₁₋₁₂-alkyloxycarbonyl, phenylcarbonyl or phenyl-C₁₋₂-alkyloxycarbonyl group and R₇ denotes a C₁₋₈-alkyl or C₅₋₇-cycloalkyl group, the tautomers, the stereoisomers and the salts thereof.
 5. Phenylamidines of general formula I according to claim 2, wherein R₆ denotes a hydroxy, C₅₋₁₂-alkyloxycarbonyl, phenylcarbonyl or benzyloxycarbonyl group and R₇ denotes a C₁₋₄-alkyl or C₅₋₆-cycloalkyl group, the tautomers, the stereoisomers and the salts thereof.
 6. The following compounds according to claim 2: (1) 4-[2-[[4-(octyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine, (2) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine, (3) 4-[2-[[4-(methyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine, (4) 4-[2-[[4-(benzoylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine and (5) 4-[2-[[4-(hydroxyamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine and the salts thereof.
 7. 4-[2-[[4-(octyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine and the salts thereof.
 8. 4-[2-[[4-(hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperazine and the salts thereof.
 9. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 8 with inorganic or organic acids or bases.
 10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 or a physiologically acceptable salt according to claim 9 optionally together with one or more inert carriers and/or diluents.
 11. Use of a compound according to at least one of claims 1 to 9 for preparing a pharmaceutical composition which is suitable for combating or preventing diseases in which smaller or larger aggregations of cells occur or cell-matrix interactions play a part.
 12. Process for preparing a pharmaceutical composition according to claim 10, characterised in that by a non-chemical method a compound according to at least one of claims 1 to 9 is incorporated in one or more inert carriers and/or diluents.
 13. Process for preparing the compounds of general formula I according to claims 1 to 9, characterised in that a. in order to prepare a compound of general formula I wherein R₆ has the meanings given in claims 1 to 8 with the exception of the hydroxy group, a compound of general formula

wherein R₇ is defined as in claims 1 to 8, is acylated with a compound of general formula Z₁—R₆′  (III), wherein R₆′ has the meanings given for R₆ in claims 1 to 8 with the exception of the hydroxy group and Z₁ denotes a nucleofugic leaving group or, if R₆′ denotes an arylcarbonyl group, Z₁ may also denote a hydroxy group, or b. in order to prepare a compound of general formula I wherein R₆ denotes a hydroxy group, a nitrile of general formula

wherein R₇ is defined as in claims 1 to 8, is reacted with hydroxylamine or the salts thereof and if necessary any protecting group using during the reactions is cleaved, and/or subsequently, if desired, a compound of general formula I thus obtained is separated into its stereoisomers and/or a compound of general formula I thus obtained is converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof. 